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  Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

Ulrich, V., Brieke, C., & Cryle, M. (2016). Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934. Beilstein Journal of Organic Chemistry, 12, 2849-2864. doi:10.3762/bjoc.12.284.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-B272-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-B273-8
Genre: Journal Article

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BeilsteinJOrgChem_12_2016_2849.pdf (Any fulltext), 8MB
 
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 Creators:
Ulrich, Veronika1, Author              
Brieke, Clara1, Author              
Cryle, Max1, Author              
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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Free keywords: crystal structure; cytochrome P450; glycopeptide antibiotic; peptide; phenolic coupling
 Abstract: The chemical complexity and biological activity of the glycopeptide antibiotics (GPAs) stems from their unique crosslinked structure, which is generated by the actions of cytochrome P450 (Oxy) enzymes that affect the crosslinking of aromatic side chains of amino acid residues contained within the GPA heptapeptide precursor. Given the crucial role peptide cyclisation plays in GPA activity, the characterisation of this process is of great importance in understanding the biosynthesis of these important antibiotics. Here, we report the cyclisation activity and crystal structure of StaF, the D-O-E ring forming Oxy enzyme from A47934 biosynthesis. Our results show that the specificity of StaF is reduced when compared to Oxy enzymes catalysing C-O-D ring formation and that this activity relies on interactions with the non-ribosomal peptide synthetase via the X-domain. Despite the interaction of StaF with the A47934 X-domain being weaker than for the preceding Oxy enzyme StaH, StaF retains higher levels of in vitro activity: we postulate that this is due to the ability of the StaF/X-domain complex to allow substrate reorganisation after initial complex formation has occurred. These results highlight the importance of testing different peptide/protein carrier constructs for in vitro GPA cyclisation assays and show that different Oxy homologues can display significantly different catalytic propensities despite their overall similarities.

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Language(s): eng - English
 Dates: 2016-09-142016-12-092016-12-272016-12-27
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: Beilstein Journal of Organic Chemistry
Source Genre: Journal
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Publ. Info: Frankfurt, Germany : Beilstein-Institut
Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: 2849 - 2864 Identifier: ISSN: 1860-5397
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000021310